Schizophrenia Research Articles

Introduction Schizophrenia (SCH) is a chronic psychiatric disorder characterized by disturbances in thought, emotion, perception, and behavior. Although gut microbiota interventions (e.g., probiotics, prebiotics, synbiotics, dietary modifications and fecal microbiota transplantation) have been widely applied in the treatment of SCH, the most effective intervention strategy remains uncertain. Methods By searching four databases, only randomized controlled trials (RCTs) were included to examine the impacts of gut microbiota interventions on SCH. The Cochrane risk-of-bias tool for randomized trials (RoB 2.0) was employed to assess the methodological quality of the included studies, RevMan5.4 was used for the meta-analysis, Stata 18 was used for sensitivity analysis, Engauge Digitizer was used to convert pictures to numbers and GRADEPro3.6 was used to grade the evidence quality. Results This study incorporated RCTs published from the earliest records up to December 2024. A total of 10 RCTs, encompassing 585 participants, were analyzed. The meta-analysis demonstrated that interventions primarily utilizing probiotics to modulate gut microbiota significantly lowered the total Positive and Negative Syndrome Scale (PANSS) scores among patients ( p = 0.001). Furthermore, substantial improvements were observed across multiple metabolic parameters: fasting blood sugar, triglycerides, total cholesterol, homeostasis model assessment of insulin resistance, and quantitative insulin sensitivity check index (all p < 0.05). While no significant effects were observed on high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, body weight, body mass index, and insulin. Conclusion This meta-analysis suggests that auxiliary probiotic interventions hold promise as an adjunctive therapy for schizophrenia, potentially yielding benefits in psychopathological, metabolic, and physiological domains. However, the current evidence remains inconclusive due to the limited number of studies, small sample sizes, and methodological variations. Firm therapeutic recommendations cannot be made at this time. The findings underscore the need for more robust, large-scale, and rigorously designed randomized controlled trials to definitively establish the efficacy and optimal protocols of auxiliary probiotic supplementation for SCH. Systematic review registration https://www.crd.york.ac.uk/PROSPERO , CRD 420250652507.

Background/Objectives: Residual symptoms—such as persistent negative or cognitive symptoms—and relapse remain common in schizophrenia (SCZ) despite the proven efficacy of antipsychotics. As a result, add-on medications are frequently prescribed in real-world clinical practice. Although these agents are often used chronically, most evidence supporting their benefits comes from short-term trials. This systematic review aimed to assess the effect of adjunctive medication on long-term clinical outcomes and relapse prevention. Methods: Following PRISMA guidelines, we searched PubMed and Scopus (2000–2025) for trials of add-on agents administered for ≥24 weeks in SCZ spectrum disorders. Eligible studies compared antipsychotic treatment as usual with and without an add-on pharmacological agent (or with an added placebo). The primary outcome was long-term symptom change evaluated via established clinical scales, while relapse was the secondary outcome. Risk of bias was assessed with the Cochrane RoB 2 tool (PROSPERO registration: CRD420251075647). Results: The 22 of 4101 selected studies were classified into a group of frequently used add-on agents in clinical practice (antidepressants, mood stabilizers) and a group of less common agents, encompassing cognitive enhancers, antibiotics and antioxidants/anti-inflammatory agents. Results regarding clinical efficacy were mixed for both groups and respective subcategories. Overall, no drug class produced robust benefits. Relapse was systematically reported in only one study, with low overall relapse rates (2.5%). Risk-of-bias assessment did not reveal significant methodological concerns, apart from high attrition (average 29.5%). Conclusions: Evidence for the long-term efficacy of add-on pharmacological treatments in SCZ is inconsistent, with no agent demonstrating reliable benefits. These findings raise concerns regarding long-term polypharmacy and also highlight the need for further investigations. Future studies should prioritize longer follow-up, relapse outcomes and realistic treatment patterns.

Introduction Immune-inflammatory dysregulations are linked to shifts in specific gut microbiota genera, underscoring the importance of the gut–brain connection in schizophrenia (SZ). However, the immune-inflammatory aspects of sex differences in SZ remain largely unexplored. The aims of this study were (1) to identify sex-related differences in inflammatory response, intestinal biomarkers, and gluten sensitivity in SZ and (2) to determine potential factors underlying variability in the immune response to gluten in this population. Methods A total of 102 individuals with SZ and 60 healthy controls (HC) were included in the study. Results Elevated titers of anti-gliadin (AGA) IgA were found in 26% of individuals with SZ compared to 22% of HC and elevated AGA IgG in 30% of SZ patients compared to 20% of HC. The IgG levels were higher in men than in women, regardless of health status. Significant differences in the levels of AGA IgG and deamidated gliadin (dGP) IgG were observed between men and women with SZ, with higher concentrations detected in men. Factors differentiating patients with positive AGA IgA antibodies included tissue transglutaminase (tTG) IgA levels, high-sensitivity C-reactive protein (hs-CRP) levels, and age. Factors associated with positive AGA IgG antibodies included dGP and anti- Saccharomyces cerevisiae (ASCA) antibody levels, negative symptoms of SZ, and age of onset. Discussion This is the first study to examine sex-related differences and illness stage in the immune response to gluten among SZ patients. Stronger inflammatory responses were found in men, suggesting sex-related disparities in gluten-related immune activation. These findings highlight a complex interplay between hormones, immune function, intestinal barrier integrity, and psychiatric symptoms. Further longitudinal research is needed to clarify these mechanisms and their clinical significance.

Bipolar disorder (BD) and schizophrenia (SZ) are complex psychiatric disorders with overlapping features. Their heterogeneity may arise from interactions between genetic variants and environmental or epigenetic modifiers. Allele-specific expression (ASE), an imbalance in expression between gene alleles, provides a key mechanism linking these interactions to disease. We conducted transcriptomic and genomic analyses in phenotype-discordant monozygotic twins to investigate ASE in psychiatric risk. Nine ASE-affected long non-coding RNAs were identified, including LINC02449, which showed a consistent allele-specific shift in BD/SZ patients favoring the alternative G allele at rs149707223. Functional analyses revealed that overexpression of the LINC02449 G allele in mice induced social deficits and repetitive behaviors. These phenotypes were associated with enhanced excitatory transmission within the mPFC-NAc circuit, mediated by the synaptic regulator CPLX1. Our findings demonstrate that ASE-driven dysregulation of LINC02449 contributes to synaptic and behavioral abnormalities, underscoring ASE as a potentially important regulatory mechanism in BD and SZ pathogenesis.

Background Insomnia has a significant impact on metabolic changes and cognitive impairments in schizophrenia (SCZ) patients. This study aimed to explore these relationships in SCZ patients. Methods A total of 609 SCZ patients were recruited. Insomnia was assessed using a self-reported questionnaire with three questions. The psychopathology and cognitive functioning were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Repeated Battery for Assessment of Neuropsychological Status (RBANS), respectively. Results SCZ patients with insomnia exhibited lower diastolic blood pressure (DBP), higher total cholesterol (TC) and poorer cognitive performance in language, attention, delayed memory and RBANS total score compared to those without insomnia (all p < 0.05). In SCZ patients with insomnia, fasting glucose contributed to immediate memory and RBANS total scores (all p < 0.05). In SCZ patients without insomnia, fasting glucose contributed to immediate memory (Beta = 0.223, t = 4.462, p < 0.001), triglycerides and DBP to visuospatial/constructional (all p < 0.05), and triglycerides to delayed memory (Beta = 0.118, t = 2.060, p = 0.040). Conclusions Our findings underscore the importance of addressing both metabolic and cognitive factors in SCZ patients with insomnia.

Background Ratios derived from uric acid (UA) and high-density lipoprotein cholesterol (HDL-C) represent novel composite indicators integrating metabolic and inflammatory information. These ratios include the uric acid-to-lymphocyte ratio (ULR), uric acid-to-HDL-C ratio (UHR), uric acid-to-creatinine ratio (UCR), uric acid-to-albumin ratio (UAR), neutrophil-to-HDL-C ratio (NHR), lymphocyte-to-HDL-C ratio (LHR), monocyte-to-HDL-C ratio (MHR), and platelet-to-HDL-C ratio (PHR). This retrospective study aimed to evaluate and compare the predictive ability of these indicators in distinguishing patients with schizophrenia (SCZ) or major depressive disorder (MDD) from healthy controls (HCs) to identify potential biomarkers. Materials and methods Blood parameter data were collected from 442 patients with SCZ, 326 with MDD, and 222 healthy controls. A retrospective analysis was conducted to examine intergroup differences in the UA- and HDL-C-derived ratios. The predictive efficacy of these parameters was assessed using receiver operating characteristic (ROC) curve analysis. Results Significant intergroup differences in biomarker levels were observed. The UHR, UAR, NHR, and MHR were identified as predictive factors for distinguishing the SCZ group from the HC group, while the UAR and MHR distinguished the MDD group from the HC group. A composite model of the UHR, UAR, NHR, and MHR in the SCZ group yielded an area under the curve (AUC) of 0.877 (p&amp;lt;0.001). Similarly, a composite model of the UAR, UCR, UHR, and MHR in the MDD group produced an AUC of 0.818 (p&amp;lt;0.001). Conclusion This study indicated that the ratio derived from UA and HDL-C more comprehensively reflects the inflammatory and metabolic status, and its expression differences can significantly distinguish SCZ and MDD.

Olanzapine-associated metabolic adverse effects lead to medication discontinuation and non-compliance in Schizophrenia (SCZ). This study aimed to examine the efficacy of a low dose of olanzapine in combination with sertraline in mitigating metabolic adverse effects by reducing the olanzapine dose in first-episode SCZ (FE-SCZ) patients. This randomized clinical trial with a blinded endpoint design was conducted among FESCZ patients. During a 12-week treatment, 196 patients with FE-SCZ were randomly assigned to the combined low-dose olanzapine/sertraline (OS group) or standard-dose olanzapine (control group). The body weight and levels of fasting glucose and blood lipids were determined at baseline and the end of weeks 4, 8, 12, and 24. Additionally, the clinical symptoms were also assessed at baseline and follow-up. Relative to the control group, the OS group had a lower percentage of weight gain from baseline to week 24 across two thresholds (7% and 10%) for changes in bodyweight (100% vs. 97.8%; 98.7% vs. 28.3%). In addition, combination treatment mitigated olanzapine-associated weight gain and other metabolic abnormalities compared with the control group (all p < 0.01). Notably, clinical symptom improvements were similar between the two treatment groups. Our study suggests that low-dose olanzapine/sertraline combination therapy was correlated with significantly less weight gain and improved other metabolic parameter levels than standard- dose olanzapine in patients with FE-SCZ. Clinical symptom improvements in the combination group were comparable to those of the olanzapine monotherapy group. These findings suggest a potential strategy to improve medication adherence and overall patient outcomes by mitigating metabolic side effects. ClinicalTrials.gov, NCT04076371.

Abstract Background Only a few studies have investigated the association of environmental factors with DNA methylation in schizophrenia (SZ). Our study sought to investigate differentially methylated positions (DMPs) and differentially methylated regions (DMRs) between patients with psychosis and healthy controls (HCs) and to explore associations of aberrant methylation levels with the Korea-Polyenvironmental Risk Score-I (K-PERS-I), a comprehensive tool measuring polyenvironmental risk factors for psychosis. Study Design Blood-based methylome-wide association study (MWAS) was conducted in patients with psychosis (n=414) and HCs (n=225). For MWAS, a new cutting-edge technique, Methyl-Seq was employed. Using the K-PERS-I, polyenvironmental risk factors were assessed. Psychosis-associated DMPs and DMRs were identified via beta-binomial regression, and their associations with K-PERS-I scores were examined. Study Results We identified 1,138 DMPs and 1,611 DMRs associated with psychosis. In the correlation analysis, 12 DMPs-annotated genes and 11 DMRs-annotated genes were associated with childhood adversity. These genes were mainly implicated in neuronal development, neurotransmitter release, synaptic plasticity, immune response and oxidative stress. For obstetric complications, most of top 5 DMPs-annotated genes were implicated in placenta function, embryonic development or gestation. For recent adult life events, top 5 DMPs- and DMRs-annotated genes were related to neurotransmitter production/release, oxidative stress and stress regulation. Conclusions We identified new psychosis-associated DMPs and DMRs. More importantly, we demonstrated how environmental factors can be biologically embedded in DNA methylation of certain genes in patients with psychosis. Ultimately, establishing causal pathways between these risk factors and DNA methylation could lead to the discovery of novel therapeutic targets.

Covarying gray and white matter networks characterize schizophrenia and bipolar disorders on a continuum: A data fusion machine learning approach and a brain network analysis.

Comparing the proteome profiling of plasma-derived extracellular vesicles in individuals with schizophrenia and healthy controls: a pilot study.

Obesity and autonomic dysfunction in schizophrenia: Associations with symptom severity and onset subtypes.

Comparative cytokine signatures and cognitive deficits in early-onset schizophrenia and adolescent major depression: Toward refined diagnostic classification frameworks.

The relationship between age of onset, peripheral plasma protein markers and social cognition in first-episode drug-naïve schizophrenia.

From variants to mechanisms: Neurogenomics in the post-GWAS era.

Protein disulfide isomerase A3 (PDIA3), a critical regulator of endoplasmic reticulum stress, was identified as a risk gene in schizophrenia (SZ). This implies the role of PDIA3 in SZ-associated immune dysregulation. We integrated Psychiatric Genomics Consortium and PsychENCODE expression quantitative trait loci data, employing summary data-based Mendelian randomization analyses to investigate PDIA3-SZ associations. Clinical characterization and C-reactive protein (CRP)-based inflammatory profiling were analyzed in people with SZ categorized by PDIA3 genotypes. Plasma PDIA3 levels were quantified and correlated with clinical profiles, CRP concentrations, and white matter density. Hierarchical linear regression with mediation modeling characterized PDIA3-CRP-cognitive interactions. Finally, LOC14 (a PDIA3 inhibitor) was administered in mice to elucidate its role in SZ-related pathobiology. PDIA3 was identified as a robust SZ risk factor, and people with SZ carrying the risk A allele of rs7174732 in PDIA3 gene exhibit more severe cognitive impairment and a trend toward higher plasma CRP levels. Plasma PDIA3 in people with SZ was positively correlated with cognition and white matter density of the hippocampus, and negatively correlated with CRP levels. Furthermore, decreased plasma PDIA3 level in people with SZ was a significant predictor of worse working memory, and CRP acted as a mediator with an 16.2% effect. Inhibition of PDIA3 in mice was associated with increased anxiety, impaired cognition, and increased power in low-frequency signals in vivo, alongside activated inflammatory responses and regulated SZ-related biological pathways. We established a PDIA3-CRP-cognitive interaction network in SZ.

Existing evidence suggests a close association between antidepressants (ATDs) and the increased incidence of psychiatric disorders. However, causality has yet to be confirmed. We aim to evaluate the causal relationship between ATDs and five psychiatric disorders using the Two-sample Mendelian Randomization (TSMR) method. This study utilized TSMR analysis to explore the causal impact of ATDs on convulsion (CONV), schizophrenia (SCZ), obsessive-compulsive disorder (OCD), substance abuse (SA), and suicide or self-harm (SOSH). The primary evaluation of causality was conducted using the Inverse Variance Weighted (IVW) method; supplementary validations were performed using the Weighted median, Weighted mode, and MR Egger methods. Sensitivity analyses, including MR-Egger intercept test, Cochran's Q test, and leave-one-out analysis, were conducted to assess potential heterogeneity and pleiotropy. The IVW method results revealed a significant positive causal relationship between genetically predicted ATDs and CONV (OR = 1.174; 95% CI 1.038, 1.328; P = 0.011), SCZ (OR = 1.177; 95% CI 1.038, 1.335; P = 0.011), OCD (OR = 1.755; 95% CI 1.355, 2.273; P = 2.06E-05), SA (OR = 1.326; 95% CI 1.222, 1.440; P = 1.61E-11), and SOSH (OR = 1.461; 95% CI 1.394, 1.532; P = 1.71E-50). The supplementary and sensitivity analyses indicated robust and reliable findings. Our study suggests that ATDs are potential risk factors for CONV, SCZ, OCD, SA, and SOSH. It is necessary to comprehensively evaluate both the therapeutic effects and potential risks of ATDs in clinical practice. Individualized treatment plans should be formulated for patients with CONV, SCZ, OCD, SA, and SOSH, with increased attention during the clinical use of ATDs.

Self-harm represents a serious psychiatric emergency frequently observed in individuals with schizophrenia, especially the paranoid subtype, where hallucinations, delusions, and comorbid depression play crucial roles. Although antipsychotic medications remain the cornerstone of treatment for symptom stabilization, they are often insufficient to address underlying psychosocial vulnerabilities that heighten self-harm risk. Supportive psychotherapy (SPT) has emerged as a cost-effective adjunctive intervention that can be integrated within primary health care to complement pharmacological treatment. This literature review synthesizes studies published between 2011 and 2025, retrieved from PubMed, ScienceDirect, and Google Scholar using the keywords paranoid schizophrenia, supportive psychotherapy, and self-harm. Findings reveal that SPT, when implemented after acute psychotic symptoms have subsided, enables patients to express emotions, receive reassurance, and modify maladaptive thoughts through supportive persuasion. Evidence indicates that SPT effectively reduces suicidal ideation and self-harm severity, commonly assessed using the Suicidal Intention Rating Scale (SIRS). Additionally, involving families and providing psychoeducation improve treatment adherence, reduce relapse rates, and create a more supportive home environment. Compared to structured psychotherapies such as cognitive behavioral therapy (CBT) or family-focused therapy (FFT), SPT is simpler, more flexible, and feasible in low-resource settings since it can be delivered by general practitioners with basic training. Overall, this review concludes that SPT offers significant potential to mitigate psychiatric emergencies and enhance the quality of life in paranoid schizophrenia patients at risk of self-harm. It recommends training primary care providers in SPT, integrating family psychoeducation, and implementing a stepped-care model that positions SPT as an initial stabilization phase before advancing to structured therapies.

Schizophrenia (SCZ) is characterized by synaptic structural deficits, yet how dysregulated noncoding RNAs (ncRNAs) drive these abnormalities remains unknown. Through integrative multilayered analysis of SCZ data from whole transcriptome sequencing (blood samples), GWAS risk loci, and expression data using pipeline ceRNAxis, the THUMPD3-AS1/miR-485-5p/ARHGAP8 axis is identified as a key regulator of synaptic function. Functional validation reveals that THUMPD3-AS1 acts as a competitive endogenous RNA, sequestering miR-485-5p and thereby derepressing ARHGAP8. Despite suppressing RhoA activity, ARHGAP8 enhances ROCK2 activation through RhoB/C-mediated compensatory mechanisms. Hyperactivation of ROCK2 through this noncanonical pathway disrupted actin cytoskeletal remodeling patterns, leading to increased immature dendritic spines and synaptic ultrastructural defects, which are pathological features associated with SCZ. In vivo, ventral hippocampal (vHip) overexpression of miR-485-5p or targeted knockdown of THUMPD3-AS1 rescued MK-801-induced SCZ-like phenotypes (anxiety, cognitive deficits, and social memory impairments) and restored synaptic ultrastructure. Crucially, this regulatory axis is cross-species conservation, with bidirectional expression changes validated in patient-derived blood and vHip tissues of mice. The findings reveal a novel ncRNA-driven pathogenic cascade in SCZ, where dysregulated RhoB/C-ROCK2 signaling, distinct from classical RhoA pathways, mediates synaptic destabilization. This presents a therapeutic axis for precision interventions targeting noncanonical actin cytoskeletal remodeling.

Subtle behavioral and cognitive symptoms precede schizophrenia (SCZ) and appear in individuals with elevated risk based on polygenic risk scores (SCZ-PRS) and family history of psychosis (SCZ-FH). However, most SCZ-PRS studies focus on European ancestry youth, limiting generalizability. Furthermore, it remains unclear whether SCZ-FH reflects common-variant polygenic risk or broader SCZ liability. Using baseline data from the Adolescent Brain Cognitive Development (ABCD) study, we investigated associations of SCZ-FH and SCZ-PRS with cognitive, behavioral, and emotional measures from NIH-Toolbox, Child Behavior Checklist (CBCL), and Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS) for 9,636 children (mean age=9.92yrs, 47.4% female), specifically, 5,636 European, 2,093 African, and 1,477 Admixed American ancestry individuals. SCZ-FH was associated with SCZ-PRS (b=0.05, FDR-p=0.02) and subthreshold psychotic symptoms (b=0.46, FDR-p=0.01) in European youth, higher CBCL scores (b range=0.36-0.6, FDR-p<0.001), and higher odds of multiple internalizing and externalizing disorders (OR=1.10-1.22, FDR-p<0.001) across ancestries. SCZ-PRS was associated with lower cognition across ancestries (b=-0.43, FDR-p=0.02), higher CBCL total problems, anxious/depressed, rule-breaking and aggressive behaviors in European youth (b range=0.16-0.33, FDR-p<0.04), and depressive disorders in Admixed American youth (OR=1.37, FDR-p=0.02). Results remained consistent when SCZ-PRS and SCZ-FH were jointly modeled. Some SCZ-FH associations weakened when income-to-needs was accounted for, suggesting that SCZ-FH may capture both genetic and environmental influences. SCZ-FH showed associations with broad psychopathology, while SCZ-PRS was associated with cognition and specific symptoms in European youth. Findings highlight their complementary role in SCZ risk assessment and the need to improve PRS utility across ancestries.

Association between biological aging and genetic susceptibility with the risk of bipolar disorder and schizophrenia: A prospective cohort study.